6-alkoxy-4-methylhexene-2-diol-1, 4 and esters thereof



Patented June 5, 1951 UNITED STATES PATENT OFFICE G-ALKOXY-I-METHYLHEXENE-2-DIOL-1,4

. AND ESTERS THEREOF Melvin S. Newman, Columbus, Ohio, assignor to Ohio State University Research Foundation, Columbus, Ohio, a corporation of Ohio No Drawing. Application May 10, 1947, Serial No. 747,179

1 14 Claims.

where R is a lower alkyl group and where Y may be either the hydroxyl group or an ester of the hydroxyl group.

The invention is specifically illustrated by processes of forming G-methoxy-4-methylhexene-2- diol-1,4 and 1-acetoxy-4-hydroxy-6-methoXy-4- methylhexene-Z.

Prior hereto there has been no recognized method of preparing the compounds referred to above. Nor have these compounds been previously synthesized nor isolated.

The products of this invention are of value in the further synthesis of other chemical compounds and are of particular value in syntheses leading to the preparation of vitamin A and derivatives of vitamin A. Prior to this invention, the products of this invention have not been known nor have there been any recognized methods for their preparation.

An object of this invention is the preparation of new intermediate chemical compounds useful in synthesizing vitamin A, esters thereof, similar compounds and other chemicals.

A further object is the provision of new methods of synthesizing various intermediates and other chemicals.

A further object is the provision of new alkoxy methylhexene diols and new acyloxy hydroxy alkoxy methylhexenes.

A further object of this invention is the preparation of a 6-a1koxy-4-methylhexene-2-dio1s-1,4.

A further object of this invention is the provision of methods for the preparation of a 6-a1koxy-4-methy1hexene-2-diols-1,4.

A further object is the preparation of monoesters of a 6-a1koxy-4-methylhexene-2-diol-1,4 such as 1-acyloxy-4-hydroxy-6-alkoxy-4-methy1- hexene-Z.

A further object is the provision of methods for the preparation of monoesters of a fi-alkoxy- 4-methy1heXene-2-diols-1,4.

The process of my invention may be more readily understood by reference to the following 2 illustrative equations, R having the value given above, M representing a metal and X representing a halogen.

( HO-CHr-CEC-H zolmM x XM o-cm-ozo-M x 20 R" In general the process disclosed in illustration of this invention comprises the formation of an alkoxy-methylhexyne diol and the reduction thereof to an alkoxy-methylhexene diol. The alkoxy methylhexene diol may be reacted with an organic acid, acid halide or acid anhydride to give an acyloxy hydroxy alkoxy methylhexene. A satisfactory way of forming the alkoxy-methylhexene diol comprises the reaction of an organometal derivative with propargyl alcohol to form a metal derivative in which one atom of the metal replaces the hydrogen of the hydroxyl group and another replaces the acetylenic hydrogen; the,

reaction of the metal derivative with an alkoxy butanone to givea metal complex addition prod- 3 uct; and the hydrolysis thereof to give the alkoxymethylhexyne diol.

Amon the metals suitable for the formation of a metal derivative of propargyl alcohol are magnesiumhalide residues (MgX) (as given in the above example), lithium and other alkali metals such as sodium and potassium, alkaline earth metals such as calcium and other metals. The metal derivatives of propargyl alcohol are suitably made by reacting propargyl alcohol with a suitable organo-metal derivative which will exa change the acetylenic hydrogen. As suggested above organo-metal derivatives s uitableas reagents for the preparation of the propargylmetal derivatives are the Grignard reagents (R'MgX) (where R is a hydrocarbon derivative) as, for example, butyhnagnesium chloride, butylmag'ne-. sium bromide and isopropyl magnesium chloride and metal alkyl (R'M) where M may be any'of the metals mentioned above. Although the preferred reagents are magnesium reagents and phenyl and butyl lithium, it is to be understood that others are within the scope er thisinvention.

The hydrogen-of-the alcohol is'also exchanged for the metal .at the same time as the hydrogen on the triple bond carbon, but on reaction with the ketone, the oxygen-metal function so formed does not undergo the addition reactions as does machete-metal function. The metal attached to the triple bond carbon upon reaction with the butanone. becomes an-oxygen-metal group. Both oxygen-metal functions are converted to hydroxyl upon hydrolysis. These metalation reactions are preferably carried out in suitable solvents. For this purpose the solvent must be inert i. e. having no replaceable hydrogen or other reactive group) and must also be anhydrous. Ethers such as diethyl ether, dibutyl ether; tetrahydrofurane; and hydrocarbons such as pentane,,hexane, benzene and toluene are among during the hydrolysis. When water alone is used metal hydroxides and basic metal salts may precipitate which may make isolation of the product diflicult. The addition of small quantities of acids suchas hydrochloric, sulfuric and acetic or of inorganic salts such as ammonium salts to the water used for hydrolysis is-advantageous as it renders these precipitates water soluble or otherwise easily removed. The preferred embodiment of this invention provides for the use of such an agent during hydrolysis, but of such kind and in such amount thatit will not react with any of the constituents of the reaction mixture in any way so as to lead to products other than those which are anobject of this inven- 1 tion.

The reduction of the alkoxy methylhexyne (1101 to the corresponding alkoxy methylhexene diol may be accomplished either chemically (such as r by solution in alcohol with a zinc copper alloy) or by the use of hydrogen and a catalyst such as a supported palladium catalyst or a Raney iron catalyst. V

The esterification of the hydroxyl group on carbon atom number one is accomplished by an acid or acid derivative such as anacid halide'or diol-1,4 with 1 mole of paranitrbphenyl' isk acya- 4 the acid anhydride which are equivalents for the esterification of the diol. Any organic ester is within the scope of this invention. However, for ease of manipulation in subsequent reactions, esters of lower molecular weight fatty acids are preferred. l I, i

The nature of the alkoxy group (OR) on the alkoxy butanone which is condensed with the metal derivative of propargyl alcohol determines the nature .of the alkoxy group in the product of this invention. The R of this group may be any hydrocarbon residue such as alkyl, cycloalkyl, aralk'yl, and aryl. In the preferred embodiment of this invention, R is a lower alkyl group such as one havingfour carbon atoms or less. The longer chain hydrocarbons are operative but in subsequent reactions may be more diflicult to handle due to higher boiling temperatures.

EXAMPLES EXAMPLE -'I W Preparation of 6-methoa:y 4'-methylhezrzmw 2-dioZ-1A A solution of 112 g. (2 mole) of propargyl alcovh'ol in 400 cc. of dry ether was added dropwise over .three ,hdurs to 2710 cc. .of a stirred solution of 1.57N (4.25 moles) butylmagnesiumchloride in ether. The solution was stirred at room temperature for an additional hour andthen a solution of 224g. (2.2 moles) of4 -m'ethoxybutanone-2 added over a period ofltwo hours. After stirring overnight, the 7 solution was hydrolyzed with 700 cc. of saturated ammonium "chloride fs'o1 n. The ether layer'wasseparated', the. oluti n was concentrated, and the residue uistineuunderre added pnes'sur'e'. H V I The product was "obtaihed iasa;yellowish oil, B. P. 122-12? '0. at 1' to 2"i'r'fm1'; 'yie1d=13215"g. (42% n =1. 4744. in

In addition 37 g. (33%) 'pr tpmpargn alcohol ('3'. P. '1"0'9'-l1' 1"C;) was recovered-"from 'thelow b'oilin'g fractions. Thest'riictufalformula of "the product is:

5 no'om o'zcJ i-cm cmo (iHfl' "EXAMPLEII 7 Preparation of 6 :methoicy 4-methy l hexe1re-2- diol-1,4 In a -'ty :lica1 experiment, 3' (os2 me1e o'f 6 methoxy l=methylhexyne diol-1,4 in -10 0 c'c. of absolute alcohol wasreduced under low hydrogen pressure using O 2*g. of a; palladium on-charcoalca'talyst: The-theoretical anew-1t offhydrogen was taken up in four ho'i'irfs,'and there was little noticeable "reaction'aftentliis -'-point. The

catalyst 'Was rem-ovedfby filtrationg' the-alcohol solvent removed, and the re'sidiie then distilled at reduced pressure. The desired product, obtained in almost quantitative "yield, distilled at 90422" C. under 1 mm. ;press re and ha'd an index of refraction n' ='1i4670. The structural formula of the product is:

CH5 7 nooH2o11:0ia-h-orrzc moon The product was characterizedby forming I a solid p-nitrophenyl urethan derivative by react ing '1 mole of the 6 methoxy-e -methylliexerie 2- 2,555,989 I 6 hate to obtain the p-nitrophenyl urethan derivamember of the class consisting of the hydroxyl tive according to the following reaction: 7 group and the fatty acid esters of the hydroxyl CH3 OH-OEI E0CH OH=OH( CH OH -OOH3-+ o,N o o-Noo H cH=o 011-011 CH3 J: oily-c C-NHGOOCHQH=CH- -OH2CH2--0OH3 OH=C H j M. P. 114.6-115.4.C., and analyzed for CH2006N2 group in which the acid component has not more as follows: than five carbon atoms.

2. As a composition of matter, compounds of Calcd. Found the formula 15 CH3 2123 815?; &2; H0-0Hr-cH=oHocH,-o:e,-ot: N 8.64 8.79

where R is a lower alkyl group. EXAMPLE III 3. As a composition of matter, compounds of Preparation of Ene-diol Acetate (1 -acetoa:y-4- the formulahydroxy-G-methomy-al-methylhexene-Z) A 500 ml. three-necked flask, mounted in an ice C aC 00CHzOH=O JJ-C 1OHi0CH: bath, was equipped with a Hershberg type stir- 5 rer, rubber stopper in one side neck, and rubber stopper bearing a calcium chloride tube in the other side neck. In the flask was placed 41 4. As a composition of matter, compounds of the formula 1 ml. (0.44 mole, 44.4 gram) of acetic anhydride. CH3 To the cold acetic anhydride was added, with HOOH CH=CH('J-CH -CHOCEI stirring 58 g. (0.36 mole) of ene-diol (6 H methoxy-4-methylhexene-2-diol 1,4) dissolved 5 As f tt d in 87.4 ml. (1.09 mole, 85.8 gram) of anhydrous th lcomposl .1011 0 ma compoun S of pyridine, freshly distilled from barium oxide. 6 0mm Stirring was continued for twenty hours, dur- 3 ing which period the ice melted, and the reaction OH COO CH CH CH J} OH CH 0R proceeded at room temperature. H

The solvents were then removed by distillation at 15 mm. During the distillation of the Where R 15 a yl roup. residue, illuminating gas was introduced into the 40 AS a c0mpos1t1on of matter a fatty acid Claisen flask through the capillary tube ester of a 6-lower alkoxy-4-methylhexene-2-dio1- 1,4 in which the acid component has not more Vapor Bath 20 than five carbon atoms. Fmtmn Temp. Temp. Pressure Welght 7. As a composition of matter, a fatty acid ester of 6-methoxy-4-methylhexene-2diol-1,4 in Mm 0mm which the acid component has not more than five S8T3 t i iii i1? 2%? "1745s carbon atoms- 95-98 114-117 1.5 25.7 1.4527 8. As a c0mpos1t1on of matter l-acetoxy--hy- 98-105 121426 M528 droxy-6-methoxy-4-methylhexene-2.

9. As a composition of matter a l-carboxyll- Since there was little difference between the h d X -B-alkoxy-4-methy1hexene2 in which the refractive indices Of fractions 2, 3 and 4, they carboxyl i derived from a fatty acid and in Were combined give a yield of 8213% of which the acid component has not more than five theoretic l. carbon atoms.

Analyslsi 10. In a method for the production of inter- Calcdf01C10H18O41 C, 59-5; H, mediates, the steps of condensing a propargyl Found: 0, 5 1 metal derivative with a l-lower alkoxy-3-buta- The Struct ral fo u a of the product 15: none, hydrolyzing the reaction product, then re- 0 CH3 ducing the hydrolyzed product and isolating the CHFJL0 CHaCH=OH & CH2OH2OCH3 60 g1;V;l:d-a1k0Xy 4 methylhexene 2 d1ol-l,4 thus H 11. In a method for the production of inter- While the forms of embodiments of the present mediates step? of condensing plopalgyl invention as herein disclosed constitute preferred metal derlvatfve Wlth lflower alkoxy-3-butaforms, it is to be understod that other forms hydrolzmg the reactlon p e remight be adopted, ,11 coming Within t scope ducmg the hydrolyzed product by the action of of the claims which follo hydrogen in the presence of a supported palla- I claim; dium catalyst and isolating the fi-lower alkoxy-4- 1. As a composition of matter, compounds of methy1heXene'2'dm1'L4 thus Obtainedthe formula 7 12. In a method for the production of inter- CH: mediates, the step of acetylating a 6-met'hoxy-4- methylhexene-2-diol-L4.

13. In a method for the production of inter- H mediates, the step of forming a fatty acid ester of where R is a lower alkyl group and where Y is a a -1 W r l y B hy -2- i -1A in five earboniatems.

which the e-acid vcomponentV ha's ,n t, 'moiie 14; In a method 'for the 'produetion oi'intermediates, the steps of condensing propargyl alcohol with a lower alkoxy butanone, hydrolyzing,

REFERENCES CITED The following references ;.;a.re 1 of :-,r.ecordin' the UNITEDHSV'IIATES PATENTS Number .Name Da .te

l 2,253,342 Mikeska et a1 Aug; 19, 1941 $369,157 Milas Feb. 13, 1945 2,369,159 Milas Feb.1l 13,. 1945 .".2;&82,085 Milas Aug. 14, 1945 2,382,086 -Milas Aug. 14, 1945 2,412,46 Milas Dec. 10, 1946 QT'HER REFERENCES J qhnson, ffAcetylenic,Compounds, vol. 1 entitled Acetylenic 'A1coh61s; 1946, published lby Arnoldand Co., London, pages 122-124. 

1. AS A COMPOSITION OF MATTER, COMPOUNDS OF THE FORMULA 